DE3104019A1 - "GLUCOSIDE DERIVATIVES" - Google Patents

Description

Gluco s idderivatβ

Of numerous. Plants are known to be hemostatic are effective. It is generally believed that their active ingredients are tannins, flavones and phospholipids. In the Investigation of the constituents of plant extracts has been made found ,, that the following compounds have a hemostatic and vascular stabilizing effect;

where R_ is a hydrogen atom or a palm! toyl group and Rg is a ß-sitosteryl, stigmasteryl or cholesteryl group is. After further investigation it was found that the physiological activities of these sterling glycosides are divided into two phases appear. It is believed that this phenomenon is due to the effects of oxidized metabolic products is.

On the basis of these findings, the research was intensively aimed at finding compounds which have a strong physiological effect, free of side effects, in particular with regard to side effects Steroid hormones are chemically and physically stable and are not readily degraded in vivo.

130051/0549

It was found according to the invention that some sterylhexopyranosides (Aglycon) with a steroid structure in which the 7-position is oxidized, strong hemostatic and vascular stabilizing Have effects that they have very low toxicity and are hardly metabolized. These connections are the oxidized Sterylglykoaidderivate according to the preceding claims.

Examples of compounds according to the invention are given in the table. A method for their extraction is given in Table 2 shown. Their acute toxicities and hemostatic and vascular stabilizing Efficacies are summarized in Tables 3 to 5.

Table 1

Connect
application no. ^R 1 ^R 2 R. ^R 4 Y R. 5 Ac Ac Ac Ac > -o 4-methylpentyl 6th Ac Ac Ac Ac > «° 3-ethyl-4-methyl
pentyl 7th Ac Ac Ac Ac > 0 3-ethyl-4-methyl
1-pentenyl 8th H H H H > »0 4-methylpenty1 9 H H H H > -o 3-ethyl-4-methyl.
pentyl 10 H H H H > = 0 3-ethyl-4-methyl
1-pentenyl 11 Ac Ac Ac Ac V ^H
'•-OH 4-methylpenty1 12th Ac Ac Ac Ac 3-Etiivl-4-methyl

Ac

H H

Ac

H H

Ac

H H

Ac

H H

/ HO

I / «/V.OH

pentyl

3-Ethyl -4-methyl-1-pentenyl

4-methylpentyl

3-ethyl-4-methyl-pentyl

3-ethyl-4-methyl- 1-pentenyl

13 0 0 51 / 0BA9

In the table above, Ac means an acetyl group,

Tabel

CHiOAc JO ₀

(IV)

13 0.0 51/0649

Connections (II):

(2) ί R = 4-methylpentyl

(3): R _g = 3-ethyl-U-methylpentyl

(4) t R_ = 3-ethyl-4-methyl-1-pentenyl

Connections (.III) χ

(5) l Rr = 4-methylpentyl

(6): R = 3-ethyl-4-methylpentyl

(7) j R ₆ . = 3-ethyl-4-methyl-1-pentenyl

Connections (IV):

(8): R = 4-methylpentyl

(9) j R = 3-ethyl-4-methylpentyl

(1O): R ₆ , = 3-ethyl-4-methyl-1-pentenyl

Connections (v) t

(11): R ₁ , R ₂ , R, R ^ = Ac, Rg = 4-methylpentyl

(12): R ₁ , R ₂ , R, R ₂ ^ = Ac, R β 3-ethyl-4-methylpentyl

(13): R ₁ , R ₂ , R-, R ^ = Ac, R_ <= 3-ethyl-4-methyl-1-pentenyl

<14): R ₁ , R ₂ , R ₃ , R 1 = H, R ₅ »A-methylpentyl

(15): R ₁ , R ₂ , R ₃ , R ^ = H, R ₅ = 3-ethyl-4-methylpentyl

(16): R, R ₂ , R, R ^ = H, R_ = 3-ethyl-4-methyl-1-pentenyl

(Ac is always an acetyl group)

The compounds (2), (3) and (h) used as starting materials in Table 2 can be obtained as follows:

You can easily by condensing cholesterol, ß-sitosterol or stigmasterine with 1-bromo-1-deoxy-2,3 »^, 6-tetraacetyl-e (-D-glucopyranose can be synthesized by the Königs-Knorr process.

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The compounds (5) »(6) and (7) can by oxidizing the corresponding starting materials with an excess amount Chromium anhydride can be obtained in pyridine as a solvent.

These compounds (5), (6) and (7) can according to suitable Methods in the compounds (8), (9) and (10) and other partial hydrolysates are hydrolyzed.

On the other hand, the compounds (5), (6) and (7) can be reduced with sodium borohydride to give the compounds (11), (12) and (I3). These compounds can be 0, ⁽¹ 5) and (i6) and other Phone! Hydrolyzed into the compounds (1 * hydrolysates welter by suitable methods.

A. Acute toxicity:

The LD _O values of the oxidized derivatives of steryo-β-D-glucoside and its acetyl derivatives were determined by the Litchfield-Wilcoxon method using male mice.

Table 3

Compound LD _n (mg / kg)

Intraperitoneally orally

5> 15,000> 12,000

8> 15,000 ^ 12,000

12> 15,000> 12,000

16> 15,000> 12,000

B. Hemoatatic Efficacy;

The influences on bleeding at the tail end of mice were investigated. There were groups of 10 males each Mice used. According to the method of Motohashi et al. (Journal of Tokyo Jikei-kai Medical College, £ 7_, (5) IO59) the tail end of each mouse was cut off by 1 cm with a sharp surgical knife and the one from the wound in

130Q51 / 0549

Blood thread leaking out of water observed. The time to complete Cessation of bleeding was measured and the ratio of reduction in bleeding time compared to that at an untreated comparison group was calculated.

Tabel k Degrading
Ratio (^) Compound dose
No. (mg / kg, i.p.) 22nd 6th 0.1 36 8th 0.1 18th 1 1 0.1 23 16 0.1 21st Sodium carbazo-
chromium sulfonate 0.0

C. Vascular stabilizing effect »

The suppression of hemorrhage in the lungs of mice was investigated. The degree of hemorrhage in the lungs of mice, which was caused by lowering the pressure to 50-0.5 now Hg / 15 see, was determined using the method of GJ Mojovski et al. (J. Pharm. Exp. Therap. 80, 1 (19 ^ 4) (notch method). From the suppression ratio, berecii_riet in comparison with an untreated comparison group, ED_ _{n of} the sample was calculated.

Table 5 (mg / kg, p.o,) link
No. ED ₅₀ 62 6th 43 10 38 14th Sodium carbazo- chromium sulfonate

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31OA019

It can be seen from this that the oxidized steryl glycoside derivatives according to the invention have a considerable hemostatic and vascular stabilizing effect. You have an extraordinary one powerful hemostatic effect on bleeding caused by various causes, and they act specifically on the vascular menibran, which is vascular stabilizing and - gives protective effects even in very small amounts. Therefore, these derivatives can be used as hemostatic agents with pretty much low toxicity, acting on bleeding caused by various causes, or as a vascular stabilizing agent Long-term drugs for dysfunction of the peripheral blood vessels, as caused by increased Vascular permeability caused by vascular weakness can be used.

These compounds can be given in the form of injections or as (solid) medicaments to be administered orally. For example, they are used as follows:

Injectionι

"Compound (8) 20 mg

NIKKOL HCO-60 *) 1.2 g

Ethanol TO ml

Glucose 5 g

The above mixture is made up to a total of 100 ml with distilled water. The injection can be made daily be administered in a dose of 2 to 10 ml in one or more doses.

Compound (8) 100 mg

NIKKOL HCO-60 *) 4g

Ethanol 5 ml

Table salt 0 »9 g

These substances are added up to a total of 100 ml » topped up with distilled water. The injection is given daily in a dose of 1 to 10 ml in one or more doses administered. 130051/0549

. ₁₀ - 31G4019

*) = Polyoxyethylene (6o) hydrogenated castor oil

Powder t

Compound (11) 1g

Lactose 99 g

300 mg to 1 g per day are given several times a day.

Tablets:

Compound (5) 2.0 mg

Lactose 20 mg

Avicel 20 mg

Magnesium stearate 0.2 mg

Strength 7 _f 8 mg

2 to 6 tablets are given several times a day.

The invention is explained in detail below with reference to examples, which, however, do not restrict the Mean scope of the invention.

example 1

Preparation of (7-ketocholesteryl) -2.3 »^» 6-tetra-0-acetylß-D-glucopyranoside (5)

5.0 g of cholesteryl-2,3,4,6-tetra-0-acetyl-ß-D-glucopyranoeid (2) were dissolved in 100 ml of carbon tetrachloride and mixed with 10 ml of acetic acid and 2.6 ml of acetic anhydride, then to 55 ml Heated to 60 C and stirred for 45 minutes. Then a solution obtained by adding 10 ml of acetic acid and 2.6 ml of acetic anhydride to a solution of tert-butyl chromate (produced from 6.8 g of chromic anhydride and 20 ml of tert-butanol) in carbon tetrachloride was added dropwise to the previous solution At the end of the addition, the reaction mixture was stirred at this temperature for 2k hours. The reaction mixture was cooled to 20 ° C and slowly with 200 ml of a 10 ^

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aqueous oxalic acid solution added. The mixture was stirred for one hour and divided into two layers. The aqueous layer was extracted with chloroform and the extract was combined with the carbon tetrachloride layer. The organic phase was washed with 5% aqueous sodium bicarbonate solution and saturated sodium chloride solution and then dried over magnesium sulfate. The solvent was distilled off. The residue was chromatographed on silica gel to obtain the title compound from a fraction eluted with a mixed solvent of benzene, η-hexane and acetone (3 13 »1). After recrystallization from ethanol, colorless crystals with a melting point of 156.4 ° C. were obtained in a yield of 50 % .

Physical Properties!

Melting point: 156.4 ° C

Infrared absorption spectrum ti " ^r (cm" )% 1750, 1680

Max

+
Mass spectrum m / e ι 730 (M)

Optical rotation Je <] ^: -58.2 ° (chloroform) Element ar analysis for C. -

Calculated C. = 67 , 19% H = 8th , 80 Found C. = 66 , 72 io H = 8th , 78 Example 2

Production of (7-ketocholesteryl) -0-D-glucopyranoside (8)

1.00 g of 7-ketocholesteryl-2,3,4,6-tetra-0-acetyl-β-D-glucopyranoside (5) was dissolved in a mixed solvent of methanol and dioxane (511). A solution of 10 mg of potassium carbonate in 20 ml of water was added dropwise with stirring at room temperature. The reaction mixture was stirred at room temperature for 1.5 hours and poured into ice water. The crystals formed in the process were filtered off. The crystals were washed with water

051/0549

and acetone, and then recrystallized from dioxane, whereby 510 mg of the title compound were obtained as colorless crystals. Exploits 66%.

Physical Properties:

Melting point: 278.0 ° C

KBr / -1

Infrared absorption spectrum V (cm "): 3 ^ 00, 1660

Max

Mass spectrum m / e: 562 (M)

Optical rotation \ θΠ ^ * -83.8 ° (pyridine) Elemental analysis for C_ "H_rO_:

Calculated C = 70.43% H = 9 »67 $> Found C β 69.22 % H = 10, O ^ #

Example 3

Preparation of (7-hydroxycholesteryl) -2.3 »^» 6-tetra-O-acetylß-D-glucopyranoside (11)

^ »0 S (7-ketocholesteryl) -2,3,4,6-tetra-0-acetyl-β-D-glucopyranoside (8) was dissolved in 500 ml of a mixture of methanol and tetrahydrofuran (3s0. 2.0 g Sodium borohydride was added to the solution at -5 ° C. with stirring, and the mixture was stirred at that temperature for 2 hours, the reaction mixture was poured into 500 ml of ether, 7% aqueous acetic acid solution was added to decompose excess sodium borohydride and ir ^ two layers separated. The organic layer was washed with 5% aqueous sodium bicarbonate solution, saturated sodium chloride solution and water and then dried over magnesium sulfate. The solvent was then distilled off. The remaining crystals were chromatographed on silica gel to obtain the title compound as the only compound from one fraction which was eluted with a solvent mixture of benzene and ether (9 * 1 to 6: 4) After recrystallization from ether or isopropanol, colorless K Crystals preserved . Yield 61 ° fa.

130051/05 * 9

KBr / -1

Physical properties

Melting point j 163.0 ° C

Infrared absorption spectrum V ^ΛΰΓ (cm ' ¹ ): 350Ot 176θ

Max

Mass spectrum m / e: 732 (M)

Optical rotation [(/ J ₁ , * -16.1 ° (chloroform

Elemental analysis for CzIiHgJi (O ₁₁ :

Calculated: C = 67.18% H = 8.80 % Found: C = 66.64 "/> H = 8.85 %

Example 4

Production of (7-hydroxycholesteryl) -ß-D-glucopyranoside (i4)

1.98 g of (7-hydroxycholesteryl) -2,3,4,6-tetra-O-acetyl-β-D-glucopyranoside (11) were hydrolyzed with potassium carbonate in the manner indicated in Example 2, 69Ο mg of the title compound being obtained became. Yield 45 % »

Physical Properties:

Melting point: 224.5 ° C. (after recrystallization from dioxane). Infrared absorption spectrum V ^r (cm) i 3500

Max

Elemental analysis for Ο- ^ Η ,, ^ Ο «:

Calculated C = 70.17 ° h H = 9.99 $> Found C = 69.63 % H = 10.32%

Other compounds can also be used in the manner described above be synthesized according to the invention. The properties of such compounds are shown in Table 6.

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31OAO19

Enamel Tabel . 6th buzz Elemental analysis ever t e 04
97 H
t compute
"found) Connect point ( ⁰ C Optical formula
) C.
(upper value
lower value cno
CV 00 8.77
9.18 application no 150.6 ) Rotation
Κξ »<°>
(Lagsmtl. ^C 43 ^H 66 ° 11 68,
67. 08
09 8.52
8.94 6th 135.1 -62.9
(Chloroform) ^C 43 ^H 64 ° 11 68,
67, 61
94 9.91
10.35 7th 26 ₅ -67.1
(Chloroform) ^C 35 ^H 58 ° 7 * 2 ^H 2 0 70,
70 04
76 9.76
9.62 9 200-205 -79.7
(Pyridine) ^C 35 ^H 56V ^4h 2 0 63,
63, 04
03 9.01
9.49 10 121-122 -80.8
(Pyridine) ^C 43 ^H 68 ° 11 68,
67, 82
14th 8.76
9.01 12th 156.6- - ^C 43 ^H 66 ° 11 00 00
VO VO 15th
39 10.23
10.31 13th 220-225 -20.2
(Chloroform) ^C 35 ^H 60 ° 7- ^H 2 ° 68,
68, 9.90
10.21 15th 209.4-
210.2 (dec -10.2
(Pyridine) ^C 35 ^H 58 ° 7 71
69 16

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Claims (7)

PATENT LAWYERS ffer grains <L Qp> ey D-8 MUNICH 22 WIDENMAYERSTRASSE □ ■ 1 BERLIN-DAHLEM 33 · PODBIELSKIALLEE Θ8 Nippon Shinyaku Co., Ltd., Kyoto (Japan) BERLIN: DIPL.-INQ. R. MÜLLER-BÖRN ER MUNICH: DIPL.-INQ. HANS-HEINRICH WEV OIPL.-INQ. EKKEHARD KORNER Munich, February 5, 1981 31 Claims X 1, oxidized steryl glycoside derivatives of the general formula R, - (D, in the R ₁ , R _? , R "and R. the same or different and a hydrogen atom or a lower alkanoyl group, Y is / UQ or Jd ₀₁₁ ^{and R} c is a 4-methylpentyl, 3-ethyl-4-methylpentyl or 3-ethyl-4-methyl-1-pentenyl group. 130051/0549 MUNICH: TELEPHONE (Ο8Θ) 225580 CABLE: PROPINDUS TELEX OS 24 244 BERLIN: TELEPHONE (O3O) Θ312ΟΘ8 CABLE: PROPINDUS -TELEX OI 84 Ο57 2. Derivatives according to claim. 1, characterized in that the Configuration of the sterol side chain in general Formula (i) is that of ß-sitosterol. 3. Derivatives according to claim 1, characterized in that the configuration of the sterol side chain in the general Formula (i) is that of Stigmasterin. k. Derivatives according to claim 1, characterized in that the configuration of the sterol side chain in the general formula (i) is that of cholesterol. 5. Derivatives according to claim 1, characterized in that the configuration of the sterol side chain in the general Formula (i) is that of β-D-glucose. 6. Derivatives according to claim 2, 3 or k _t, characterized in that the configuration of the sugar member in the general formula (i) is that of ß-D-glucose. 7. Hemostatic and vascular stabilizing, on the circulatory organs active drugs, containing the oxidized Steryl glycoside derivatives according to Claims 1 to 6 as the main active component. 130051/0549